Chronic low dose aspirin use decreases colorectal cancer (CRC) risks. It is uncertain how chemoprevention by aspirin and other NSAIDs mechanistically reduce CRC risks. We propose that NSAIDs reduce CRC risks by augmenting natural anticancer crypt niche defenses. Crypt niches inherently reduce cancer risks with a stem cell hierarchy where stem cells are a minority of all cells. Random stem cell turnover (neutral drift) further reduces average numbers of stem cells per crypt and can also eliminate mutant stem cells via differentiation. Anything that increases neutral drift should decrease cancer risks by decreasing average stem cell numbers. We propose to test this hypothesis in a new mouse model that can measure stem cell neutral drift rates. Mutations (Apc) that predispose to cancer should slow neutral drift rates whereas NSAIDs, by modulating crypt niche signaling, should increase neutral drift rates, decreasing average stem cell numbers and cancer risks. Verifying that neutral drift rates correlate with cancer risks will identify the stemcell niche as a new specific chemoprevention target. A mouse model of neutral drift will facilitate the rapid testing of new drugs or dosing schedules that can effectively reduce average stem cell numbers with fewer side effects. Chemoprevention that augments natural crypt anticancer mechanisms is more likely to have fewer side effects than cytotoxic strategies. PUBLIC HEALTH RELEVANCE: We propose that NSAIDs prevent colorectal cancer by enhancing normal crypt anticancer mechanisms that inherently minimize average stem cell numbers though random stem cell turnover (neutral drift). This hypothesis will be tested in a new mouse model that allows neutral drift measurements---mutations that predispose to cancer should slow neutral drift, whereas NSAIDs should increase neutral drift, decreasing average stem cell numbers and cancer risks.